Regulating
inflammatory
microglia
presents
a
promising
strategy
for
treating
neurodegenerative
and
autoimmune
disorders,
yet
effective
therapeutic
agents
delivery
to
these
cells
remains
challenge.
This
study
investigates
modified
lipid
nanoparticles
(LNP)
mRNA
hyperactivated
microglia,
particularly
those
with
pro-inflammatory
characteristics,
utilizing
supervised
machine
learning
(ML)
classifiers.
We
developed
screened
library
of
216
LNP
formulations
varying
compositions,
N/P
ratios,
hyaluronic
acid
(HA)
modifications.
The
transfection
efficiency
eGFP
was
assessed
in
the
BV-2
murine
cell
line
under
different
immunological
states,
including
resting
activated
conditions
(LPS-activated
IL4/IL13-activated).
ML-guided
morphometric
analysis
tracked
phenotypes
various
subtypes
before
after
transfection.
Four
ML
classifiers
were
investigated
predict
phenotypic
changes
based
on
design
parameters.
Multi-Layer
Perceptron
(MLP)
neural
network
emerged
as
best-performing
model,
achieving
weighted
F1-scores
≥0.8.
While
it
accurately
predicted
responses
from
LPS-activated
cells,
struggled
IL4/IL13-activated
cells.
MLP
model
validated
by
predicting
performance
four
unseen
delivering
BV2
HA-LNP2
optimal
formulation
target
IL10
mRNA,
effectively
suppressing
phenotypes,
evidenced
shifts
morphology,
increased
expression,
reduced
TNF-α
levels.
also
evaluated
human
iPSC-derived
confirming
its
efficacy
modulating
responses.
highlights
potential
tailored
techniques
enhance
therapy
neuroinflammatory
disorders
leveraging
carrier's
immunogenic
properties
modulate
microglial
Journal of Nanobiotechnology,
Год журнала:
2024,
Номер
22(1)
Опубликована: Июнь 28, 2024
Abstract
Lipid
nanoparticles
(LNPs)
have
proven
themselves
as
transformative
actors
in
chimeric
antigen
receptor
(CAR)
T
cell
therapy,
surpassing
traditional
methods
and
addressing
challenges
like
immunogenicity,
reduced
toxicity,
improved
safety.
Promising
preclinical
results
signal
a
shift
toward
safer
more
effective
CAR
treatments.
Ongoing
research
aims
to
validate
these
findings
clinical
trials,
marking
new
era
guided
by
LNPs
utility
therapy.
Herein,
we
explore
the
preference
for
over
methods,
highlighting
versatility
of
their
delivery
nucleic
acids.
Additionally,
address
key
considerations,
heralding
Graphical
Gene
and
RNA-based
therapeutics
represent
a
promising
frontier
in
oncology,
enabling
targeted
modulation
of
tumor-associated
genes
proteins.
This
review
explores
the
latest
advances
payload
vectorization
delivery
systems
developed
for
vivo
cancer
treatments.
We
discuss
viral
non-viral
organic
particles,
including
lipid
based
nanoparticles
polymeric
structures,
effective
transport
plasmids,
siRNA,
self-amplifying
RNA
therapeutics.
Their
physicochemical
properties,
strategies
to
overcome
intracellular
barriers,
innovations
cell-based
carriers
engineered
extracellular
vesicles
are
highlighted.
Moreover,
we
consider
oncolytic
viruses,
novel
capsid
modifications,
approaches
that
refine
tumor
targeting
immunomodulation.
Ongoing
clinical
trials
regulatory
frameworks
guide
future
directions
emphasize
need
safe,
scalable
production.
The
potential
convergence
these
with
combination
therapies
paves
way
toward
personalized
medicine.
ACS Nano,
Год журнала:
2023,
Номер
17(15), С. 15025 - 15043
Опубликована: Июль 23, 2023
CRISPR/Cas9
systems
have
great
potential
to
achieve
sophisticated
gene
therapy
and
cell
engineering
by
editing
multiple
genomic
loci.
However,
efficient
multiplex
editing,
the
delivery
system
needs
adequate
capacity
transfect
all
RNA
species
at
required
stoichiometry
into
cytosol
of
each
individual
cell.
Herein,
inspired
biomineralization
in
nature,
we
develop
an
all-in-one
biomimetic
mineralized
system.
This
allows
for
precise
control
over
coencapsulation
ratio
between
Cas9
mRNA
sgRNAs,
while
also
exhibiting
a
high
loading
capacity.
In
addition,
it
enhances
storage
stability
4
°C
up
one
month,
surface
nanoparticles
can
be
easily
functionalized
targeting
vivo
nonliver
sites.
Based
on
above
characteristics,
as
proof-of-concept,
our
was
able
significant
gene-editing
target
(Survivin:
31.9%,
PLK1:
24.41%,
HPV:
23.2%)
promote
apoptosis
HeLa
cells
mouse
model,
inhibiting
tumor
growth
without
obvious
off-target
effects
liver
tissue.
addresses
various
challenges
associated
with
multicomponent
vivo,
providing
innovative
strategy
RNA-based
editing.
Advanced Materials,
Год журнала:
2023,
Номер
36(13)
Опубликована: Ноя. 6, 2023
Abstract
Messenger
RNA
(mRNA)‐based
therapy
has
emerged
as
a
powerful,
safe,
and
rapidly
scalable
therapeutic
approach
that
involves
technologies
for
both
mRNA
itself
the
delivery
vehicle.
Although
there
are
some
unique
challenges
different
applications
of
therapy,
common
challenge
all
therapeutics
is
transport
into
target
cell
cytoplasm
sufficient
protein
expression.
This
review
focused
on
behaviors
at
cellular
level
nanotechnology‐mediated
systems,
which
have
not
been
comprehensively
reviewed
yet.
First,
four
main
introduced,
including
immunotherapy,
replacement
genome
editing,
reprogramming.
Second,
types
cargos
systems
summarized.
Third,
strategies
to
enhance
efficiency
during
trafficking
process
highlighted,
accumulation
cell,
internalization
endosomal
escape,
release
from
nanocarrier,
translation
protein.
Finally,
opportunities
development
presented.
can
provide
new
insights
future
fabrication
nanocarriers
with
desirable
performance.
Abstract
The
advent
of
SARS-CoV-2
variants
with
defined
mutations
that
augment
pathogenicity
and/or
increase
immune
evasiveness
continues
to
stimulate
global
efforts
improve
vaccine
formulation
and
efficacy.
extraordinary
advantages
lipid
nanoparticles
(LNPs),
including
versatile
design,
scalability,
reproducibility,
make
them
ideal
candidates
for
developing
next-generation
mRNA
vaccines
against
circulating
variants.
Here,
we
assess
the
efficacy
LNP-encapsulated
booster
encoding
spike
protein
concern
(Delta,
Omicron)
using
a
predecessor
(YN2016C
isolated
from
bats)
strain
elicit
durable
cross-protective
neutralizing
antibody
responses.
mRNA-LNP
have
desirable
physicochemical
characteristics,
such
as
small
size
(~78
nm),
low
polydispersity
index
(<0.13),
high
encapsulation
efficiency
(>90%).
We
employ
in
vivo
bioluminescence
imaging
illustrate
capacity
our
LNPs
induce
robust
expression
secondary
lymphoid
organs.
In
BALB/c
mouse
model,
three-dose
subcutaneous
immunization
mRNA-LNPs
achieved
remarkably
levels
cross-neutralization
Omicron
B1.1.529
BA.2
extended
periods
time
(28
weeks)
good
safety
profiles
all
constructs
when
used
regime,
YN2016C
bat
virus
sequences.
These
findings
important
implications
design
aim
trigger
immunity
current
newly
emerging
ImmunoHorizons,
Год журнала:
2024,
Номер
8(1), С. 97 - 105
Опубликована: Янв. 1, 2024
Abstract
Chimeric
Ag
receptor
(CAR)
NK
cells
are
challenging
to
manufacture
and
fail
achieve
consistent
tumor
infiltration
sustained
cytolytic
function
in
the
microenvironment.
In
vivo
engineering
of
using
mRNA-based
CAR
delivery
may
overcome
these
issues.
this
study,
we
developed
an
programming
method
by
designing
CARs
that
leverage
biology
cell
receptors
for
type–specific
expression
function.
These
were
engineered
fusion
a
recognition
domain
with
natural
cytotoxic
family
including
NKp30,
NKp44,
NKp46.
Our
results
demonstrated
receptor–based
can
engage
endogenous
signaling
adaptors
effectively
activate
human
lysis
cytokine
production.
Specifically,
discovered
stable
NKp44-based
was
contingent
on
presence
immune
cell–specific
adaptor
DAP12.
This
innovative
strategy
facilitates
direct
situ
cells,
enhancing
safety
minimizing
off-target
effects
nontargeted,
healthy
tissues.
Nanoscale,
Год журнала:
2023,
Номер
16(5), С. 2250 - 2264
Опубликована: Дек. 26, 2023
Messenger
RNA
(mRNA)-based
therapeutic
agents
have
demonstrated
significant
potential
in
recent
times,
particularly
the
context
of
COVID-19
pandemic
outbreak.
As
a
promising
prophylactic
and
strategy,
polypeptide-based
mRNA
delivery
systems
attract
interest
because
their
low
cost,
simple
preparation,
tuneable
sizes
morphology,
convenient
large-scale
production,
biocompatibility,
biodegradability.
In
this
review,
we
begin
with
brief
discussion
synthesis
polypeptides,
followed
by
review
commonly
used
polypeptides
delivery,
including
classical
cell-penetrating
peptides.
Then,
challenges
against
extracellular,
intracellular,
clinical
barriers,
are
discussed
detail.
Finally,
highlight
range
strategies
for
offering
valuable
insights
into
advancement
carrier
development.
